title: Tumor-targeting with novel non-benzoyl 6-substituted straight chain pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis.
abstract: A new series of 6-substituted straight side chain pyrrolo[2,3-d]pyrimidines 3a-d with varying chain lengths (n = 5-8) was designed and synthesized as part of our program to provide targeted antitumor agents with folate receptor (FR) cellular uptake specificity and glycinamide ribonucleotide formyltransferase (GARFTase) inhibition. Carboxylic acids 4a-d were converted to the acid chlorides and reacted with diazomethane, followed by 48% HBr to generate the α-bromomethylketones 5a-d. Condensation of 2,4-diamino-6-hydroxypyrimidine 6 with 5a-d afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 7a-d. Hydrolysis and subsequent coupling with diethyl l-glutamate and saponification afforded target compounds 3a-d. Compounds 3b-d showed selective cellular uptake via FRα and -β, associated with high affinity binding and inhibition of de novo purine nucleotide biosynthesis via GARFTase, resulting in potent inhibition against FR-expressing Chinese hamster cells and human KB tumor cells in culture. Our studies establish, for the first time, that a side chain benzoyl group is not essential for tumor-selective drug uptake by FRα.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Christina
authors.initials: C
authors.lastname: Cherian
authors.forename: Steven
authors.initials: S
authors.lastname: Orr
authors.forename: Shermaine
authors.initials: S
authors.lastname: Mitchell-Ryan
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Hou
authors.forename: Sudhir
authors.initials: S
authors.lastname: Raghavan
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D008958:Models, Molecular; D015394:Molecular Structure; D011685:Purine Nucleotides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058975:Folate Receptor 1; D005493:Folic Acid Antagonists; D011685:Purine Nucleotides; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D005492:Folic Acid